The American Cancer Society estimated that in 2010 over 32,000 men have died of prostate cancer.1 Metastasis is the primary cause of death due to prostate cancer, and the most common site is bone.2 Bone metastases are incurable and associated with significant pain and morbidity. The mechanisms by which prostate cancer cells metastasize and grow in bone are not fully understood, but we hypothesize that the Wnt signaling pathways are essential.3-8 While Wnt signaling in prostate cancer bone metastases has been shown to stimulate epithelial-mesenchymal transition (EMT) and the typical osteoblastic phenotype of the metastases, its role is still unclear.9-11 Understanding the role of Wnt signaling will lead to new therapeutic targets in the prevention or treatment of bone metastasis in prostate cancer and will decrease its morbidity and mortality. This project is designed to test the central hypothesis that the Wnt signaling pathways and DKK-1 (an inhibitor of canonical and stimulator of noncanonical Wnt signaling) are important for regulation of prostate cancer proliferation, progression, and metastasis to bone. The three aims are designed to test whether: 1) Autocrine non-canonical Wnt signaling by prostate cancer increases tumor growth;2) Paracrine canonical Wnt signaling by prostate cancer induces osteoblastic metastases;and 3) Factors released by bone resorption, in cooperation with the noncanonical Wnt pathway, promote prostate cancer growth and metastasis. We have developed a unique mouse model of prostate cancer using the canine Ace-1 prostate cancer cells to test the hypotheses. Ace-1 cells metastasize exclusively to long bones and the spine and induce osteoblastic bone metastases. In addition, the hypotheses will be tested using two-compartment in vitro co-cultures of mouse calvaria and prostate cancer cells and vossicle (neonatal mouse vertebrae)/prostate cancer co-implantation in nude mice. The proposed F32 fellowship research training plan will provide a strong basic-translational science research experience for Jessica Simmons, DVM. Dr. Simmons is an aspiring scientist whose research interests are focused in investigating the pathogenesis of prostate cancer metastases in the bone. The F32 fellowship will support Dr. Simmons'research studies as well as augment her career development. PUBLIC HEALTH RELEVANCE: Wnt signaling modulates the bone microenvironment in both development and disease. Unraveling the dialogue between of Wnt signaling between metastatic prostate cancer cells and the bone microenvironment will help elucidate new treatment targets. The results of our specific aims will be relevant to the understanding the pathogenesis of prostate cancer metastasis and discovery of new therapeutic targets for the prevention or inhibition of bone metastasis.